Malaria kills more than 1 million children annually with most deaths attributable to Plasmodium falciparum. Yet despite years of intensive research, an efficacious vaccine against falciparum malaria remains elusive. A small animal model of human malaria would greatly enhance progress toward our understanding of the human immune response to malaria, as well as providing a readily available model for screening this much needed vaccine. The goal of this proposal is to develop a humanized mouse model of malaria. To achieve this, we will select between two potential humanized mouse models that reconstitute the human adaptive immune system, as well as circulate human erythrocytes that are targets for the replication of P. falciparum. The two humanized mouse models to be tested are: (1) human cord blood stem cells transplanted intravenously into irradiated neonatal NOD/scidltz/IL2R3null mice and (2) fetal human thymus and liver tissue engrafted under the renal capsule of irradiated adult NOD/scidltz/IL2R3null mice followed by the intravenous injection of homologous liver stem (CD34+) cells. Recent findings indicate that human CD45+ leukocytes and human glycophorin A+ erythrocytes are readily detectable in the blood of the engrafted mice, indicating that these models will likely: (1) support P. falciparum replication, and (2) elicit measurable human cell- and antibody-mediated immune responses to P. falciparum. To compare these two humanized mouse models of P. falciparum malaria, we will analyze the magnitude, time course and outcome of P. falciparum parasitemia and relate parasitemia to the developing human immune responses. The results of the proposed research will establish a humanized mouse model that will provide new opportunities to identify protective components of the immune system responding to blood-stage infection. The results of these studies will help to target mechanisms, cells, and/or molecules of the human immune system for future malaria vaccine design. PROJECT NARRATIVE: The goal of this proposal is to develop a humanized mouse model of malaria. The results of the proposed research will provide new opportunities to identify protective components of the immune system responding to blood-stage infection, and then target mechanisms, cells, and/or molecules of the human immune system for future malaria vaccine design.